Pharmaceutical compounds which are highly lipophilic present considerable formulation challenges. Because of their low solubility in aqueous media, including the contents of the mammalian digestive tract, they often suffer from poor or variable bioavailability when given orally or via other routes that require transmembrane absorption. Examples of such medicinal compounds include the immunosuppressants cyclosporine and FK506 (tacrolimus); protease inhibitors such as ritonavir; central nervous system drugs such as tiagabine; and anti-inflammatory agents such as zileuton and other 5-lipoxygenase inhibitors.
One method of formulating lipophilic compounds is to combine them with glyceride carriers which form emulsions upon mixing with water. Emulsions are described, for example, in U.S. Pat. No. 4,388,307 issued to Cavanak, a commercial example of which is the cyclosporine-containing product SANDIMMUNE.RTM. oral solution. This product comprises the emulsifier LABRAFIL.RTM. (a polyoxyethylated kernel oil), olive oil and alcohol, with the compound cyclosporin A present at a concentration of 100 mg/ml. Cavanak suggests that such glyceride carriers may assist in alleviating problems of physical instability such as precipitation of the drug from solution, and may also enable higher plasma concentrations.
More recently, it has been proposed that a preferred vehicle for lipophilic compounds is the so-called "self-emulsifying drug delivery system" which, when exposed to an aqueous medium, forms a fine oil-in-water emulsion with little or no agitation. The property of self-emulsification permits such formulations to be administered in concentrated form, as for example in a hard gelatin or soft elastic capsule, with the expectation that a fine emulsion will be formed in the digestive tract. Moreover, it has been suggested that self-emulsifying formulations, when given orally, may offer improvements in both the rate and extent of absorption of the medicinal compound and can result in reduced variability in plasma concentration profiles. (See, S. A. Charman el al., Pharmaceutical Research 9(1):87-93 (1992), and N. H. Shah et al., International Journal of Pharmaceutics 106:15-23 (1994).) Additionally, emulsions which have been prepared by combining a self-emulsifying pre-concentrate with an aqueous medium appear to benefit, due to their small droplet diameter, from improved physical stability when compared with conventional emulsions.
Previously-disclosed self-emulsifying systems include those in which a lipophilic drug is combined with mixtures of (i) medium-chain triglycerides and nonionic surfactants, (ii) vegetable oils and partial glycerides such as polyglycolyzed glycerides or medium-chain mono- and diglycerides, or (iii) vegetable oils and nonionic surfactants such as polysorbate 80 or PEG-25 glyceryl trioleate. Other formulations have been characterized as self-emulsifying, including the above-mentioned SANDIMMUNE.RTM. cyclosporine formulation; however, these additionally contain a substantial amount of a solubilizing agent or solvent such as ethanol, rendering them unsuitable for certain uses such as filling into gelatin capsules, from which the solvent can readily escape.
Self-emulsifying formulations which seek to overcome this drawback are disclosed by Hauer et al in U.S. Pat. No. 5,342,625. In these formulations, a "microemulsion pre-concentrate" of a cyclosporine is formed by combining the drug with (I) a hydrophilic phase, (II) a lipophilic phase, and (III) a surfactant, as well as optional thickeners, anti-oxidants or other excipients. Unfortunately, the complexity of these ternary formulations may make them costly and difficult to manufacture.
There exists, consequently, a need for formulations of lipophilic drugs such as cyclosporines that are simpler and easier to prepare than the ternary systems described above. Orban et al., in PCT Publication No. WO 92/09299, propose homogenized cyclosporine-containing formulations that comprise propylene glycol, ethanol and a polyoxyethylene/polyoxypropylene block copolymer, while Fleck et al., in PCT Publication No. WO 94/23733, disclose cyclosporine formulations containing CREMOPHOR and/or TRANSCUTOL. However, additional formulations are sought which offer an advantageous combination of physical stability, desirable pharmacokinetics and/or ease of manufacture.